1. Technical Field
The present invention is concerned with process control synthesis of volatile anesthetics. Volatile anesthetics generally include desflurane, sevoflurane, isoflurane, enflurane and nitrous oxide. Synthesis of the widely used anesthetics desflurane, sevoflurane and isoflurane involve the chlorination and fluorination of precursor molecules to eventually yield the final products.
2. Background Art
Commercially available volatile fluorinated anesthetics include desflurane (CF3CHFOCHF2), enflurane (CHClFCF2OCHF2), halothane (CF3CHBrCl), isoflurane (CF3CHCIOCHF2) and sevoflurane ((CF3)2CHOCH2F). The physical properties of volatile fluorinated anesthetics are important to the anesthesiologist. These physical properties include boiling point, specific gravity, vapor density, vapor pressure, oil/gas partition coefficient and blood/gas partition coefficient (percent of the anesthetic found in a known quantity of blood versus the percent found in a known volume of atmosphere above the blood sample).
Although each of the molecules depicted above has its own unique characteristics that provide a set of parameters needed to commercially develop it as an anesthetic, the chemical properties and chemical purity of the fluorinated volatile anesthetic are particularly important.
The chemical purity of the fluorine substituted volatile anesthetic is of utmost importance, requiring clean methods of production and extensive manufacturing controls. Additionally, the synthesis of these anesthetics requires consideration of many factors not normally encountered in the medicinal chemistry arena, i.e., the need to produce millions of pounds of pharmaceuticals with the highest standards of purity. Accordingly, it is highly desirable to find synthetic routes that give high purity fluorine substituted volatile anesthetics.
Desflurane, 2-(difluoromethoxy)-1,1,1,2-tetrafluoroethane, is an inhalation anesthetic possessing very advantageous properties. Desflurane is of significant commercial value, in particular, as a result of being an effective anesthetic which demonstrates rapid induction and an unexpectedly rapid recovery from anesthesia. The latter property makes it especially attractive for surgical procedures done on an out-patient basis. The use of desflurane as an inhalation anesthetic is claimed in Terrell, U.S. Pat. No. 4,762,856, issued Aug. 9, 1988. Desflurane was originally disclosed in Example XXI of Russell et al U.S. Pat. No. 3,897,502, issued Jul. 29, 1975, which is directed to a method of fluorinating ethers to make compounds generally useful as solvents, degreasing agents and the like.
More recently, a number of processes for preparing desflurane have been patented. Halpern et al, U.S. Pat. No. 4,855,511 discloses preparing desflurane by the reaction of a compound having the formula CHCl2OCHClCOCl with sulfur tetrafluoride at elevated temperatures. Halpern et al, U.S. Pat. No. 4,874,901 discloses a method of fluorinating a chlorine on the carbon adjacent the ether oxygen in chloro-fluoro ethers by reaction with sodium or potassium fluoride at elevated temperature and pressure in the absence of solvent. By this method, isoflurane is converted to desflurane.
In Robin et al, U.S. Pat. No. 4,972,040, fluoral methyl hemiacetal, CF3CH(OH)OCH3, is reacted with p-toluene sulfonyl chloride to form the corresponding tosylate compound. The tosylate group is then removed by reaction with a fluorinating agent to form CF3CHFOCH3. This compound is converted to desflurane by chlorinating the methyl group, preferably with chlorine gas, followed by reaction with a fluorinating agent.
Robin et al. U.S. Pat. No. 5,015,781, disclosed a process for forming desflurane by the direct fluorination of isoflurane by bromine trifluoride. Cicco, U.S. Pat. No. 5,026,924, discloses a low temperature preparation of desflurane comprising reacting isoflurane with hydrogen fluoride in the presence of a catalyst comprising antimony pentachloride, alone or in combination with antimony trichloride.
Rozov et al., U.S. Pat. No. 5,283,372 discloses the preparation of desflurane by reacting an optically pure isoflurane with bromide trifluroide to yield a corresponding optically pure desflurane. Chambers et al., U.S. Pat. No. 6,054,626, discloses the preparation of desflurane by reacting CF3CH2OCHF2 with Cobalt trifluroide. Rozov et al., U.S. Pat. No. 5,205,914, discloses the preparation of desflurane by using the starting material hexafluoropropene.
Isoflurane synthesis and purification methods are disclosed in U.S. Pat. No. 3,720,587; 3,726,268; and 3,846,332.
During 2003, 615 batches of acetone from an isoflurane purification process were processed by Baxter Healthcare Corporation (Guayama, Puerto Rico), 18 of which failed the water specification, leading to significant delays pending the investigation and documentation of each failed batch. There is, therefore, a need for an improved processes for the synthesis and purification of volatile anesthetics.